The proposal consists of two distinct projects: a study of long- term neurotransmitter-relatd modifications of the CNS as a result of chronic drug exposure, and a study of the electrophysiological mechanisms of action of the cannabinoids. The chronic drug studies will include the cannabinoids, cocaine, amphetamine and morphine, and will focus on the phenomenon of "reverse tolerance." The first aim of the proposal is to define the relationship between the dosage regimen and the develoment of "reverse tolerance," and the persistence of "reverse tolerance." "Reverse tolerance" to cocaine and amphetamine will be described in terms of three effects, locomotor stimulation, stereotypy and anticonvulsant activity; the cannabinoids, in terms of anticonvulsant activity; and morphine, locomotor stimulation. Potential mechanisms will be investigated by two different approaches: Neurotransmitter-related drugs will be tested for long-term changes in their pharmacodynamics, which will be quantitatively assessed from dose-response data. The second approach is to measure quantitively, be receptor autoradiography, specific neurotransmitter-related receptors in "reverse-tolerant" animals. The autoradiographic analysis of receptor binding will be restricted to those transmitter systems that appear to have modified function, as determined by the results of the neurotransmitter-related drug studies. The results should yield data on potential mechanisms of "reverse tolerance" for the various drugs, as well as provide a rational basis for identification of drug interactions in "reverse-tolerant" animals. The aims of the electrophysiological studies are to extend our on- going study of the influence of the cannabinoids on single synapses to an assessment of effects on postsynaptic neurotransmitter- and voltage-gated ionic conductances. Postsynaptic neurotransmitter-gated conductances will be determined by two different methods, the analysis of synaptic noise and the patch- clamp technique; voltage-gated conductances will be assessed by the patch-clamp technique. The synaptic-noise experiments will be conducted on frog, rat and lobster neuromuscular junctions; the patch-clamp experiments, on individual frog toe-muscle fibers and rat hippocampal neurons. The conductance data may provide the ionic basis for some of the excitatory and depressant effects of cannabinoids.